Platinum(II) anticancer agents such as cisplatin, carboplatin and oxaliplatin presently in clinical use are among the most widely used anticancer agents in the world. In particular, these platinum drugs have been known to exhibit superior antitumor activities against genital cancers such as testicular, ovarian, and bladder cancers as well as colorectal cancer.
However, like other low molecular weight anticancer agents such as paclitaxel, doxorubicin, etc., platinum anticancer agents administered systemically attack not only tumor cells and tissues but also normal cells and tissues equally without tumor selectivity, which cause severe toxicities such as nephrotoxicity, neurotoxicity, etc. In addition, their acquired cross-resistance and low water-solubility seriously limit their utility for cancer treatment (D. Lebwohl, R. Canetta, Eur. J. Cancer., 34, 1522 (1998)).
Accordingly, tremendous efforts have recently been made worldwide for the development of tumor targeting anticancer agents having selective cytotoxicity only on tumor cells or tissues, thereby drastically reducing adverse effects resulting from toxicity and overcoming drug-resistance. One of the most rational approaches to overcome non-selectivity and drug resistance inherently associated with the low molecular weight anticancer agents currently in clinical use is to use polymeric drug delivery systems, which have been intensively studied for the last decade. As representative examples, there are two different methods to afford the low molecular weight anticancer agents to have tumor selectivity. One is direct coupling of the conventional anticancer agents with a targeting group having a strong affinity to receptors or antigens preferentially expressed in tumor cells or tissues, or coupling both a targeting group and a conventional anticancer agent with a water-soluble polymer (Active Targeting), and the other method to confer tumor selectivity on an anticancer agent is to conjugate the small molecular anticancer agent directly to polymer particles which have not any targeting group but exhibit enhanced permeability and retention (EPR) effect in tumor tissues (Passive Targeting).
In particular, since the discovery that polymers with appropriate molecular weights show preferentially enhanced permeability and retention effect in solid tumor tissues (H. Meada, and Y. Matsumura, CRC Crit, Rev. Ther. Drug Carrier Sys 6, 193 (1989)), a great deal of researches have been performed worldwide for the development of new polymeric materials showing high tumor selectivity. Two probable reasons why polymers with appropriate molecular weights show high selectivity to tumor tissues are as follows:
The first one is that although large polymer molecules, nano-particles or the like can hardly permeate through blood vessel walls in normal tissues composed of regularly and tightly arrayed cells, they can permeate through the blood vessel pores into the tumor tissues due to the coarse vasculature of the tumor tissues, flow of a large amount of blood into the tumor tissues, and higher vascular pressure in tumor tissues.
The second one is that there is no lymphatic vessel as a discharge path for polymer particles in tumor tissues. Therefore, in tumor tissues, it is difficult for polymer particles permeated therein to be discharged unlike in normal cells (R. Duncan, Pharm. Sci. Technol. Today, 2, 441 (1999)). As a result, polymer particles permeated through the blood vessel pores are selectively accumulated in tumor tissues (H. Maeda, J. Fang, T. Inutsuka, Inter Immun., 3, 319 (2003)), yielding higher selectivity of polymers to tumor tissues.
Accordingly, a great deal of researches has been performed for the development of new drug delivery systems using specific bio-affinitive polymer materials around the world (A. S. Lundberg and R. A. Weinberg, Eur, J, Cancer, 35, 531-539 (1999)). One successful example of such attempts is neocarzinostatin bound to styrene-maleic anhydride copolymer (SMANCS), which was early developed and commercialized in Japan (K. Tsuchia, H. Maeda, Urology, 55, 495 (2000)). Furthermore, various types of polymer-drug conjugates, including a conjugate of N-(2-hydroxypropyl)methacrylamide (HPMA) and doxorubicin (P. A. Vasey, C. Twelves, Clin. Cancer Res., 5, 83 (1999)), have been developed and recently entered clinical trials (R. Haag, F. Kratz, Angew. Chem. Int. Ed., 2006, 45, 1198-1215). Therefore, it can be seen that researches in this field have been actively progressing worldwide. However, how many of such conjugate drugs can be approved finally for clinical use is questionable, because most of the conventional organic polymers used as drug carriers are not biodegradable and have not high tumor selectivity.
The present inventors discovered that cyclotriphosphazene derivatives grafted with equimolar amounts of a poly(ethylene glycol) (PEG) as a hydrophilic group and an amino acid as a hydrophobic group exhibited thermosensitive properties (Youn Soo Sohn et al. J. Am. Chem. Soc., 2000, 122, 8315), and successfully prepared a thermosensitive platinum anticancer agent therefrom for local delivery by conjugating the antitumor (diamine)platinum moiety to the amino acid of the cyclic trimer (Youn Soo Sohn et al. J. Control. Release, 90, 303 (2003); Youn Soo Sohn et al. U.S. Pat. No. 6,333,422 (2001)). However, the resultant cyclotriphosphazene-platinum conjugate drug did not exhibit tumor selectivity in the biodistribution experiment, probably because the conjugate molecules could not aggregate to form micelles or nanoparticles due to the low hydrophobicity of the amino acid employed as a hydrophobic group.